Feedback Control of Bifurcations in Spatially-Extended Cardiac Muscle

在这个多学科项目中，来自生物医学工程、儿科心脏病学、物理学和数学的研究人员将结合理论和实验方法来研究快速起搏下心脏反应的稳定性。随着起搏频率的增加，心肌的动作电位持续时间 (APD alternans) 会出现逐次变化。 APD 交替及其临床表现（T 波交替）与心律失常的易感性增加相关。因此，通过拟议的研究增加对节律稳定性的了解将导致检测心律失常先兆和识别有颤动和心动过速风险的患者的新技术的开发。具体目标是：（1）开发一种新的、更稳健的实验方案来确定心脏反应模式的稳定性。 (2) 研究在空间延伸的同质组织中发生的稳态交替是否总是不一致（即组织某些区域的 APD 振荡与起搏部位的振荡异相）。 (3)构建基于光纤的透壁映射系统，允许在三个维度上映射动作电位。该研究将从使用理想化膜动力学模型的数学分析开始。分析结果将通过计算机模拟进行测试，首先涉及空间钳条件下的理想化膜模型，然后发展到最多三个空间维度的生理精确膜模型。一些模型还将考虑跨壁 APD 异质性。同时，将对分析结果进行实验测试。最初的测试将使用牛蛙心室的体外制备物（相对而言），并进展到兔心室的体外楔形制备物，其表现出哺乳动物心脏典型的跨壁APD异质性和各向异性。理论、计算机模拟和实验研究结果之间的三向比较将使我们能够完善并在需要时扩展数学理论和计算机模型，每次迭代都会使我们更全面地了解心脏动力学。

In this multidisciplinary project, researchers from Biomedical Engineering, Pediatric Cardiology, Physics, and Mathematics will combine theoretical and experimental approaches to investigate the stability of cardiac response under rapid pacing. As the pacing rate increases, cardiac muscle exhibits beat-to-beat changes in the action potential duration (APD alternans). APD alternans and its clinical manifestation, T-wave alternans, are associated with increased vulnerability for arrhythmias. Thus, increased understanding of the rhythm stability coming from the proposed research will lead to the development of new techniques for detection of the precursors of arrhythmias and for identifying patients at risk for fibrillation and tachycardias. Specific Aims are: (1) Develop a new, more robust experimental protocol for determining stability of the cardiac response pattern. (2) Investigate whether steady-state alternans occurring in spatially extended, homogeneous tissue is always discordant (i.e., APD oscillations in some regions of the tissue are out of phase with the oscillations at the pacing site). (3) Construct an optical fiber-based transmural mapping system that allows mapping action potentials in three dimensions. The research will start with mathematical analysis that uses idealized models of membrane kinetics. Analytical results will be tested through computer simulations, first involving idealized membrane models under space clamp conditions, then progressing to physiologically accurate membrane models in up to three spatial dimensions. Some models will also take into account transmural APD heterogeneity. Concurrently, analytical results will be tested experimentally. Initial tests will use in-vitro preparations of bullfrog ventricle, which are relatively, and progress to in-vitro wedge preparations of rabbit ventricle, which exhibit transmural APD heterogeneity and anisotropy typical for mammalian hearts. The three-way comparisons between results from theory, computer simulations, and experimental studies will allow us to refine and, if needed, expand the mathematical theory and computer models, with each iteration leading to more complete understanding of cardiac dynamics.